CHOLESTEROL-BIOSYNTHESIS FROM LANOSTEROL - DIFFERENTIAL INHIBITION OFSTEROL DELTA(8)-ISOMERASE AND OTHER LANOSTEROL-CONVERTING ENZYMES BY TAMOXIFEN

The fact that administration of tamoxifen (Tam) to humans and laborato ry animals (e.g., rats and monkeys) results in both a drastic reductio n in cholesterol and a marked accumulation of certain sterol intermedi ates in their serum led us to undertake more direct biochemical studie s on the mechanism of Tamps inhibitory action on the cholesterogenic e nzymes. Of the five rat hepatic lanosterol-converting enzymes examined , the enzyme most sensitive to inhibition by Tam was sterol Delta(8)-i somerase (Delta(8)-SI) (a 208-fold inhibition relative to lanosterol ( 14)alpha-methyl demethylase), followed by sterol Delta(24)-reductase ( 13-fold) and sterol Delta(14)-reductase (5.2-fold), The inhibition pat terns of all four affected enzymes were found to be noncompetitive, de spite widely different inhibition constants (K-i) of 0.21 to 23.5 mu M . The inhibitory activity of Tam on Delta(8)-SI was not affected by de tergent-mediated solubilization of the microsomes. In Chinese hamster ovary cells, inhibition of Delta(8)-SI activity (IC50 = 0.15 mu M) was paralleled by a decreased rate of [C-14]-mevalonate incorporation int o cholesterol (IC50 = 0.70 mu M) Our results should provide more insig ht into an underlying mechanism of Tam's cardioprotective role by inte rfering the operation of the pathway of cholesterol biosynthesis from lanosterol in mammals.